Deep eutectic solvents for antiepileptic drug phenytoin solubilization: thermodynamic study

Thermodynamic investigations provide information about the solute-solvent interactions in the selection of the proper solvent for different fields of pharmaceutical sciences. Especially, the study of antiepileptic drugs in solutions (ethanol/co-solvent) has been a subject of interest owing to their effect in the systems using interaction with a number of important biological membranes. This work focuses on the measurement of density and speed of sound of the phenytoin (PTH) in ethanol/deep eutectic solvents (choline chloride:ethylene glycol, and choline chloride:glycerol) solutions as the innovative class of green solvents at temperature range (288.15 to 318.15) K. It was determined Hansen solubility parameters for assessment of PTH interactions in the solvent media. Some thermophysical parameters including apparent molar volumes Vϕ, apparent molar isobaric expansion \documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$$E_\varphi^0$$\end{document}Eφ0, and Hepler’s constant, apparent molar isentropic compressibility κφ were obtained and calculated using these data. To correlate the Vϕ and κφ values, the Redlich-Meyer equation was used to calculate the number of quantities containing standard partial molar volume and partial molar isentropic compressibility. Finally, \documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$$\Delta \delta$$\end{document}Δδ values showed a strong interaction between PTH and solvent (ethanol/DES (ChCl:EG)). The thermodynamic analysis of the studied system also plays a crucial role in the pharmaceutical industry.

where M (kg mol -1 ), and m (mol kg -1 ) are the molar mass and the molality of the PTH. The d 0 (kg m -3 ) and d (kg m -3 ) are also density of solvent (ethanol and DESs + ethanol) and density of the solutions. The values of V ϕ for the mentioned systems at all worked temperatures are given in Table 1. For the binary PTH + ethanol and ternary PTH/ethanol/DESs solutions, the V ϕ values have a downward trend at all temperatures. Figure 2 indicate the V ϕ values for binary PTH + ethanol and ternary PTH/ethanol/DESs (with molalities 0.5 and 1.5 mol kg -1 ) solutions at T = 298.15 K. The positive values of V ϕ decreased with rising of the PTH molalities. The reduction in the values of V ϕ with increasing temperature causes more attraction for DESs, which is evidence of strong interactions between PTH and solvent. According to the calculated results, it is clear that the values of V ϕ also decreased with increasing DES amount. This behavior may be due to the attenuation of the interactions between PTH and the ethanol molecule that occur by increasing the concentrations of DESs. The intermolecular forces between PTH and ethanol are reinforced due to functional groups and various ionic groups in DESs.
The following relation, known as the Redlich-Meyer equation, is used to determine the standard partial molar volume V 0 ϕ for PTH 15 : where B v is the empirical parameter of the equation. The least-squares analysis was used to obtain the V 0 ϕ and B v parameters, which were presented in Table 2. The obtained values of V 0 ϕ represent the solute-solvent interactions. In Fig. 3, variations of V 0 ϕ are demonstrated for each system at DESs molality m = 1 mol kg -1 versus the worked temperature. The obtained parameters show that the V 0 ϕ values are similar to the V ϕ values decreasing with increasing temperature and decreasing with increasing DES molalities.
The partial molar transfer � tr V 0 φ is another essential quantity to express useful information about interactions. The � tr V 0 φ for PTH in the studied systems has been evaluated as follow: The partial molar transfer volumes � tr V 0 φ are listed in Table 2. Based on the developed model by Friedman and Krishnan 16,17 , the hydration cospheres overlap in the polar-nonpolar and nonpolar-nonpolar groups decreases the volume while the hydration cospheres overlap between polar groups or two ionic groups enhances volume. The obtained values for the systems studied in this work are negative and decrease with increasing in DESs molalities, which explains the superiority of nonpolar-nonpolar and polar-nonpolar interactions over the rest.
The polynomial equation was applied for the temperature dependence V 0 ϕ values as follow 18 :  , which were given in Table 3. The apparent molar isobaric expansion E 0 ϕ was calculated using the derivative relative to the temperature of Eq. (4) 19 : The second derivative of V 0 ϕ relative to temperature is an important quantity to explain the structure breaking or making properties that developed by Hepler as follow 21 : Table 4 reports the obtained values of ∂ 2 V 0 ϕ ∂T 2 p for studied systems. The values of this constant for the all systems are positive that indicates the performance of PTH is as structure making in the presence of ethanol and DESs. The trend for PTH in the presence of DESs is as follows; ChCl:EG ˃ ChCl:Gly. The experimental density and speed of sound data were used to calculate the isentropic compressibility, κ s (Pa -1 ). This quantity is due to the resistance of the fluid to changes in pressure and consequently to changes in density and volume. Laplace-Newton's equation was applied to compute κ s as follow 22 :     Table 5.
According to the results in Table 5, it can be seen that the κ φ values decreased with increasing PTH molalities and also with increasing temperature. The interactions for PTH and solvent can also be explained using these values. Finally, the κ φ values were correlated using the Redlich-Meyer equation as follow 24 .
where, κ 0 φ and B κ are the partial isentropic compressibility and equation parameter, respectively. The obtained parameters are given in Table 6. Figure 4, shows the values of κ 0 φ versus the temperature. This quantity, like the V 0 ϕ expresses PTH-solvent interactions. The κ 0 ϕ values are decreased with increasing temperature in the all studied systems.
The partial molar transfer isentropic compressibility � tr κ 0 φ for PTH in the systems is obtained as follow: These � tr κ 0 φ values are listed in Table 8. Hansen solubility parameters results. Hansen solubility parameters are one of the most important methods for investigation of solute interaction in the presence of solvent. With these parameters, the appropriate solvent can be selected. Hildebrand first introduced solubility parameters that "similar solves similar" 25 . This parameter is modified by Hansen 26 and is used as the Hildebrand-Hansen parameter. Solubility parameters are determined experimentally or by calculations as follow: where ΔH vap , V m , and E coh are the evaporation enthalpy, the molar volume and the intermolecular forces (adhesion energy), respectively. Also, R and T are the general constant of the gases and the temperature.
The introduced solubility parameter is expressed as follow; failure of hydrogen bonds between molecules (δ h ), adjacent intermolecular forces (bipolar interactions) (δ p ), and adhesion energy density, from the sum of energies required to overcome scattering forces (δ d ): The mutual solubility between solute i and solvent j is calculated as follow: to determine δ h , δ p , and δ d , methods based on structural contributions of functional groups are used. Thus, δ d is estimated from the following relation: where F d is the constant dispersion component of molar adsorption. The interactions of polar groups are also expressed by using the following equation: where, F p is the constant polar component of molar adsorption. δ h can also be determined as follow: In this study, the parameters δ d , δ p and δ h were estimated from sources and some were obtained using the Krevelen and Hoftyzer method 28,29 for PTH drug, DESs and ethanol, which are collected in the Table 7. Differences between drug solubility parameter and solvents (ethanol and ethanol/DESs) are calculated from Eq. (14) and are reported in the Table 8. As can be seen from the results in Table 8, �δ values indicating a strong interaction between PTH and solvent (ethanol/DES (ChCl:EG)) relative to others systems.  Table 1 summarized the information of the chemicals applied in this work. It should be mentioned that the purity of the all chemicals is provided by the suppliers ( Table 9).

Experimental
The purified compounds of EG or Gly as HBDs and ChCl as HBA were mixed with the molar ratio 1:2 in the water bath at temperature about 333 K for 4 h until a colorless and homogeneous liquid formed 11 . For the prepared DESs composition, the uncertainty of less than 5·10 -2 mol was estimated. Using the Karl − Fisher titration technique (method TitroLine KF), the water content was measured for the prepared DESs. Eventually, a vacuum pump was used to remove moisture and excess impurities of the DESs. Some of the properties of DESs (ChCl:Gly and ChCl:EG) are listed in Table 10.
Apparatus and procedure. All solutions were prepared by filling tight glass vials, which are containing different amounts of the PTH in the water and ternary DESs solutions. In this regard, an analytical balance with precision 10 -4 g (AW 220, GR220, Shimadzu, Japan) was used.
The molality of PTH was introduced as follows; mole of PTH per kg of solvent (binary in ethanol and ternary in DESs/ethanol solutions). For all of the prepared solutions, the uncertainty was estimated to be less than 5·10 -4 mol·kg -1 .
Density and speed of sound measuring device of Anton Paar Co. (with model DSA 5000, Austria) at the frequency (approximately 3 MHz) was utilized for all the binary (PTH/ethanol) and ternary (PTH/DESs/ethanol) solutions. After washing the device with deionized water and ethanol and drying with air, the device was calibrated using degassed and deionized water at the T = 293.15 K and atmospheric pressure. A Peltier device embedded inside the apparatus has been utilized to keep the temperature of the samples with an accuracy of 0.001 K. The standard uncertainties for density and speed of sound measurements were estimated to be 0.015 kg m -3 and 1 m s -1 , respectively 20 . The measured data for the DESs used in this work were compared with the data reported in the literature and are given in Table 10. The data are well matched and in an acceptable range. Uncertainties are also given for the data reported in the relevant tables.

Conclusions
The most important part of drug preparation and production is the investigation of the interactions that occur between the drug and the solvent. In this regard, the volumetric and compressibility properties were applied to describe these interactions. As can be understood from the results of V 0 ϕ and κ 0 ϕ values, the interaction between Table 5. Experimental speed of sounds u data and partial molar isentropic compressibility,κ φ values for PTH molalities m PTH (mole of PTH per 1 kg of ethanol for binary system and mole of PTH per 1 kg of DESs/ethanol solutions for ternary system) in binary PTH/ethanol and ternary PTH/DESs (ChCl:Gly and ChCl:EG)/ethanol solutions at T = (288.15 to 318.15) K and ambient pressure (P = 871 hPa). Standard uncertainties (u) for each variable are u (T) = 0.001 K; u (m) = 0.0005 mol kg -1 ; u (p) = 10 hPa. The combined standard uncertainty for the average of n speed of sound measurements u (u) = 1 m s -1 . Standard uncertainty (u) for DESs composition was estimated to be less than 5·10 -2 mol ratio. a m is the molality of PTH, mole of PTH per 1 kg of solvents.       Table 10. Some of the physical properties of DESs (binary mixtures) used in the work at 298.15 K and pressure (p = 871 hPa). Standard uncertainties (u) for each variable are u (T) = 0.001 K; u (p) = 10 hPa. The combined standard uncertainty for the average of n density measurements u (ρ) = 0.015 kg m -3 and speed of sound u (u) = 1 m s -1 . Standard uncertainty (u) for DESs composition was estimated to be less than 5·10 -2 mol ratio. a Molar mass of DESs = x 1 M 1 + x 2 M 2 . x 1 and M 1 ; mole fraction and molar mass of ChCl. x 2 and M 2 ; mole fraction and molar mass of HBD. The melting point is expressed for the solidus (formation of the first liquid) or liquids (disappearance of last crystals). The density and speed of sound were measured for the liquid state of the prepared DESs.